Abstract 4570: Role of ERRalpha in ovarian cancer

Abstract

Abstract Objective. The estrogen receptor-related receptor-alpha (ERRα, encoded by ESRRA) has emerged as a key transcriptional regulator of mitochondrial function and has been implicated as a prognostic marker in many cancers, including epithelial ovarian cancer. ERRα has shown promise as a therapeutic target in breast cancer where ERRα transcriptional activity regulates growth of breast cancer cells. This study aims to evaluate whether ERRα expression in ovarian cancer correlates with patient outcomes, determine the effect of inhibiting ERRα transcriptional activity on ovarian cancer cell growth, and identify molecular signaling pathways regulated by ERRα in ovarian cancer cells. Methods. Affymetrix U133A gene expression microarray analysis from frozen tumor specimens of serous epithelial ovarian cancer was used to compare ESRRA transcripts levels in patients with short-term (<3 years) verses long-term survival (>7 years). ESRRA transcript levels were also measured in normal ovarian surface and fallopian tube epithelial tissues. Protein expression levels were assessed in ovarian cancer cell lines and patient tumor samples. Overall survival was estimated using the Kaplan-Meier Method. The effect of ERRα inhibition on proliferation and anchorage-independent growth was determined after treatment with the ERRα antagonist, XCT790. The activity of 49 different phospho-receptor tyrosine kinases (RTKs) was analyzed after down-regulation of ERRα with shRNA. Results. ESRRA expression was significantly higher in cancer tissues verses normal ovarian surface and fallopian tube epithelial tissues. Expression was also higher in patients with short-term versus long-term survival. Inhibition of ERRα with XCT790 led to a >50% reduction in proliferation and anchorage-independent growth. The induced knockdown of ERRα decreased the phosphorylation of RTKs, including HER2, suggesting that important growth promoting pathways are downstream of ERRα. Conclusions. In this study we determined that higher expression of ESRRA correlates with worse survival in ovarian cancer patients. However, inhibition of ERRα results in decreased growth potential. This effect may be manifest through the regulation of receptor tyrosine kinase activity. Thus, ERRα may be an important therapeutic target for the treatment of ovarian cancer and warrants future studies to determine the role of ERRα regulated signaling networks in ovarian oncogenesis. Citation Format: Ellen V. Stevens, Regina Whitaker, Audrey Guinet, Ching-Yi Chang, Carole Grenier, Jeffrey Marks, Donald P. McDonnell, Susan K. Murphy, Andrew Berchuck, Stephanie Gaillard. Role of ERRalpha in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4570. doi:10.1158/1538-7445.AM2014-4570